Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

AbstractEosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after single-stranded RNA (ssRNA) stimulation of the TLR-7–MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF)–7 and eosinophil-associated ribonucleases EAR-1 and EAR-2. Hypereosinophilia in the airways of infected mice also correlated with increased expression of IRF-7, IFN-β, and NOS-2, and inhibition of NO production with the NOS-2 inhibitor L-NMA partially reversed the accelerated virus clearance promoted by eosinophils. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virus-induced lung dysfunction.

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Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long Live Attenuated Vaccine Candidates

Virologica Sinica ◽

10.1007/s12250-021-00345-3 ◽

2021 ◽

Author(s):

Li-Nan Wang ◽

Xiang-Lei Peng ◽

Min Xu ◽

Yuan-Bo Zheng ◽

Yue-Ying Jiao ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Gene Deletion ◽

Human Respiratory Syncytial Virus ◽

Temperature Sensitive ◽

T7 Promoter ◽

Vaccine Candidates ◽

Rsv Infection ◽

Syncytial Virus

AbstractHuman respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract illness (LRTI), and no vaccine against LRTI has proven to be safe and effective in infants. Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice. The constructed recombinant plasmids harbored (5′ to 3′) a T7 promoter, hammerhead ribozyme, RSV Long strain antigenomic cDNA with cold-passaged (cp) mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain (A2cpts) or further combined with SH gene deletion (A2cptsΔSH), HDV ribozyme (δ), and a T7 terminator. These vectors were subsequently co-transfected with four helper plasmids encoding N, P, L, and M2-1 viral proteins into BHK/T7-9 cells, and the recovered viruses were then passaged in Vero cells. The rescued recombinant RSVs (rRSVs) were named rRSV-Long/A2cp, rRSV-Long/A2cpts, and rRSV-Long/A2cptsΔSH, respectively, and stably passaged in vitro, without reversion to wild type (wt) at sites containing introduced mutations or deletion. Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed temperature-sensitive (ts) phenotype in vitro and in vivo, all rRSVs were significantly attenuated in vivo. Furthermore, BALB/c mice immunized with rRSVs produced Th1-biased immune response, resisted wtRSV infection, and were free from enhanced respiratory disease. We showed that the combination of ΔSH with attenuation (att) mutations of cpts contributed to improving att phenotype, efficacy, and gene stability of rRSV. By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains, we have laid an important foundation for the development of RSV live attenuated vaccines.

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Inhibitory Effect of Sargassum fusiforme and Its Components on Replication of Respiratory Syncytial Virus In Vitro and In Vivo

Viruses ◽

10.3390/v13040548 ◽

2021 ◽

Vol 13 (4) ◽

pp. 548

Author(s):

Kiramage Chathuranga ◽

Asela Weerawardhana ◽

Niranjan Dodantenna ◽

Lakmal Ranathunga ◽

Won-Kyung Cho ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Antiviral Agent ◽

Active Components ◽

Sargassum Fusiforme ◽

Antiviral Effects ◽

Improve Life Expectancy ◽

Rsv Infection ◽

Syncytial Virus

Sargassum fusiforme, a plant used as a medicine and food, is regarded as a marine vegetable and health supplement to improve life expectancy. Here, we demonstrate that S. fusiforme extract (SFE) has antiviral effects against respiratory syncytial virus (RSV) in vitro and in vivo mouse model. Treatment of HEp2 cells with a non-cytotoxic concentration of SFE significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and syncytium formation. Moreover, oral inoculation of SFE significantly improved RSV clearance from the lungs of BALB/c mice. Interestingly, the phenolic compounds eicosane, docosane, and tetracosane were identified as active components of SFE. Treatment with a non-cytotoxic concentration of these three components elicited similar antiviral effects against RSV infection as SFE in vitro. Together, these results suggest that SFE and its potential components are a promising natural antiviral agent candidate against RSV infection.

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RESPIRATORY SYNCYTIAL VIRUS LUNG INFECTION IN INFANTS: IMMUNOREGULATORY ROLE OF INFECTED ALVEOLAR MACROPHAGES

PEDIATRICS ◽

10.1542/peds.96.2.391 ◽

1995 ◽

Vol 96 (2) ◽

pp. 391-391

Author(s):

Leon S. Greos

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Lung Injury ◽

Alveolar Macrophages ◽

Lung Infection ◽

Local Immune Response ◽

Rsv Infection ◽

Syncytial Virus

Alveolar macrophages are infected by RSV in vivo and coexpress potent immunomodulatory molecules that potentially regulate local immune response or lung injury caused by RSV infection.

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Lentiviral and AAV-mediated Expression of Palivizumab Offer protection against Respiratory Syncytial Virus infection

10.21203/rs.3.rs-558941/v1 ◽

2021 ◽

Author(s):

Agata Antepowicz ◽

Omar Habib ◽

Freja Kirsebom ◽

Cecilia Johansson ◽

Deborah R. Gill ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vulnerable Populations ◽

The Elderly ◽

Complete Protection ◽

Adeno Associated Virus ◽

Common Cause ◽

Immunodeficiency Virus ◽

Rsv Infection ◽

Syncytial Virus

Abstract Respiratory syncytial virus (RSV) infection is a common cause of hospitalisation in infants and the elderly. Palivizumab prophylaxis is the only approved treatment modality but is costly and only offered to select vulnerable populations. Here, we investigated gene delivery approaches via recombinant adeno-associated virus (rAAV2/8) and simian immunodeficiency virus (rSIV.F/HN) vectors to achieve sustained in vivo production of palivizumab in a murine model. Delivery of palivizumab-expressing vectors 28 days prior to RSV challenge resulted in complete protection from RSV-induced weight loss. This approach offers prophylaxis against RSV infection, allowing for wider use and reduction in treatment costs in vulnerable populations.

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Pathogenesis of Respiratory Syncytial Virus Infection in BALB/c Mice Differs Between Intratracheal and Intranasal Inoculation

Viruses ◽

10.3390/v11060508 ◽

2019 ◽

Vol 11 (6) ◽

pp. 508 ◽

Cited By ~ 1

Author(s):

Elisabeth A. van Erp ◽

Anke J. Lakerveld ◽

H. Lie Mulder ◽

Willem Luytjes ◽

Gerben Ferwerda ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Animal Models ◽

Antiviral Agents ◽

Mouse Strains ◽

Immunological Parameters ◽

Intranasal Inoculation ◽

Rsv Infection ◽

Syncytial Virus ◽

Tract Disease

Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease requiring hospitalization in infants. There are no market-approved vaccines or antiviral agents available, but a growing number of vaccines and therapeutics are in (pre)clinical stages of development. Reliable animal models are crucial to evaluate new vaccine concepts, but in vivo RSV research is hampered by the lack of well-characterized animal models that faithfully mimic the pathogenesis of RSV infection in humans. Mice are frequently used in RSV infection and vaccination studies. However, differences in the use of mouse strains, RSV subtypes, and methodology often lead to divergent study outcomes. To our knowledge, a comparison between different RSV inoculation methods in mice has not been described in the literature, even though multiple methods are being used across different studies. In this study, we evaluated various pathological and immunological parameters in BALB/c mice after intratracheal or intranasal inoculation with RSV-A2. Our study reveals that intranasal inoculation induces robust pathology and inflammation, whereas this is not the case for intratracheal inoculation. As immunopathology is an important characteristic of RSV disease in infants, these data suggest that in mice intranasal inoculation is a more appropriate method to study RSV infection than intratracheal inoculation. These findings will contribute to the rational experimental design of future in vivo RSV experiments.

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Targeting the Respiratory Syncytial Virus N0-P Complex with Constrained α-Helical Peptides in Cells and Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00717-20 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Marie Galloux ◽

Nadège Gsponer ◽

Vanessa Gaillard ◽

Brice Fenner ◽

Thibaut Larcher ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Small Molecules ◽

Mechanisms Of Action ◽

Rsv Infection ◽

Macrocyclic Peptides ◽

Escape Mutants ◽

Severe Respiratory Infection ◽

Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is the main cause of severe respiratory infection in young children worldwide, and no therapies have been approved for the treatment of RSV infection. Data from recent clinical trials of fusion or L polymerase inhibitors for the treatment of RSV-infected patients revealed the emergence of escape mutants, highlighting the need for the discovery of inhibitors with novel mechanisms of action. Here we describe stapled peptides derived from the N terminus of the phosphoprotein (P) that act as replication inhibitors. We demonstrate that these peptides inhibit RSV replication in vitro and in vivo by preventing the formation of the N0-P complex. The present strategy provides a novel means of targeting RSV replication with constrained macrocyclic peptides or small molecules and is broadly applicable to other viruses of the Mononegavirales order.

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Dual Proinflammatory and Antiviral Properties of Pulmonary Eosinophils in Respiratory Syncytial Virus Vaccine-Enhanced Disease

Journal of Virology ◽

10.1128/jvi.01536-14 ◽

2014 ◽

Vol 89 (3) ◽

pp. 1564-1578 ◽

Cited By ~ 15

Author(s):

Yung-Chang Su ◽

Dijana Townsend ◽

Lara J. Herrero ◽

Ali Zaid ◽

Michael S. Rolph ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

The Elderly ◽

Pulmonary Eosinophilia ◽

Recurrent Wheezing ◽

Interleukin 5 ◽

Lower Respiratory Tract Disease ◽

Syncytial Virus ◽

Tract Disease ◽

Deficient Mice

ABSTRACTHuman respiratory syncytial virus (RSV) is a major cause of morbidity and severe lower respiratory tract disease in the elderly and very young, with some infants developing bronchiolitis, recurrent wheezing, and asthma following infection. Previous studies in humans and animal models have shown that vaccination with formalin-inactivated RSV (FI-RSV) leads to prominent airway eosinophilic inflammation following RSV challenge; however, the roles of pulmonary eosinophilia in the antiviral response and in disease pathogenesis are inadequately understood.In vivostudies in mice with eotaxin and/or interleukin 5 (IL-5) deficiency showed that FI-RSV vaccination did not lead to enhanced pulmonary disease, where following challenge there were reduced pulmonary eosinophilia, inflammation, Th2-type cytokine responses, and altered chemokine (TARC and CCL17) responses. In contrast to wild-type mice, RSV was recovered at high titers from the lungs of eotaxin- and/or IL-5-deficient mice. Adoptive transfer of eosinophils to FI-RSV-immunized eotaxin- and IL-5-deficient (double-deficient) mice challenged with RSV was associated with potent viral clearance that was mediated at least partly through nitric oxide. These studies show that pulmonary eosinophilia has dual outcomes: one linked to RSV-induced airway inflammation and pulmonary pathology and one with innate features that contribute to a reduction in the viral load.IMPORTANCEThis study is critical to understanding the mechanisms attributable to RSV vaccine-enhanced disease. This study addresses the hypothesis that IL-5 and eotaxin are critical in pulmonary eosinophil response related to FI-RSV vaccine-enhanced disease. The findings suggest that in addition to mediating tissue pathology, eosinophils within a Th2 environment also have antiviral activity.

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56 NMSO3, a potent inhibitor of respiratory syncytial virus (RSV) infection in vitro and in vivo

Antiviral Research ◽

10.1016/s0166-3542(00)90387-5 ◽

2000 ◽

Vol 46 (1) ◽

pp. A52

Keyword(s):

Respiratory Syncytial Virus ◽

Potent Inhibitor ◽

Rsv Infection ◽

Syncytial Virus

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Role of CCL11 in Eosinophilic Lung Disease during Respiratory Syncytial Virus Infection

Journal of Virology ◽

10.1128/jvi.79.4.2050-2057.2005 ◽

2005 ◽

Vol 79 (4) ◽

pp. 2050-2057 ◽

Cited By ~ 41

Author(s):

Stephen P. Matthews ◽

John S. Tregoning ◽

Anthony J. Coyle ◽

Tracy Hussell ◽

Peter J. M. Openshaw

Keyword(s):

Respiratory Syncytial Virus ◽

Cytokine Production ◽

The Elderly ◽

Viral Pathogen ◽

Blocking Antibody ◽

Interleukin 5 ◽

Lung Eosinophilia ◽

Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a major viral pathogen of infants and the elderly. Significant morbidity is caused by an overexuberant mixed lung cell infiltrate, which is thought to be driven by chemokines. One of the main chemotactic mediators responsible for the movement of eosinophils is CCL11 (eotaxin). Using a mouse model of eosinophilic bronchiolitis induced by RSV, we show here that treatment in vivo with a blocking antibody to CCL11 greatly reduces lung eosinophilia and disease severity. In addition, anti-CCL11 caused a striking inhibition of CD4-T-cell influx and shifted cytokine production away from interleukin-5 without reducing the resistance to viral replication. These results suggest that in addition to influencing eosinophil diapedesis and survival, anti-CCL11 has an action on T cells. These studies strengthen the case for anti-CCL11 treatment of Th2-driven diseases.

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